title: Fas-mediated apoptosis regulates the composition of peripheral alphabeta T cell repertoire by constitutively purging out double negative T cells.
abstract: BACKGROUND
  The Fas pathway is a major regulator of T cell homeostasis, however, the T cell population that is controlled by the Fas pathway in vivo is poorly defined. Although CD4 and CD8 single positive (SP) T cells are the two major T cell subsets in the periphery of wild type mice, the repertoire of mice bearing loss-of-function mutation in either Fas (lpr mice) or Fas ligand (gld mice) is predominated by CD4(-)CD8(-) double negative alphabeta T cells that also express B220 and generally referred to as B220+DN T cells. Despite extensive analysis, the basis of B220+DN T cell lymphoproliferation remains poorly understood. In this study we re-examined the issue of why T cell lymphoproliferation caused by gld mutation is predominated by B220+DN T cells.
  
  
  RESULTS
  We combined the following approaches to study this question: Gene transcript profiling, BrdU labeling, and apoptosis assays. Our results show that B220+DN T cells are proliferating and dying at exceptionally high rates than SP T cells in the steady state. The high proliferation rate is restricted to B220+DN T cells found in the gut epithelium whereas the high apoptosis rate occurred both in the gut epithelium and periphery. However, only in the periphery, apoptosis of B220+DN T cell is Fas-dependent. When the Fas pathway is genetically impaired, apoptosis of peripheral B220+DN T cells was reduced to a baseline level similar to that of SP T cells. Under these conditions of normalized apoptosis, B220+DN T cells progressively accumulate in the periphery, eventually resulting in B220+DN T cell lymphoproliferation.
  
  
  CONCLUSIONS
  The Fas pathway plays a critical role in regulating the tissue distribution of DN T cells through targeting and elimination of DN T cells from the periphery in the steady state. The results provide new insight into pathogenesis of DN T cell lymphoproliferation.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Abdiaziz S
authors.initials: AS
authors.lastname: Mohamood
authors.forename: Dylan
authors.initials: D
authors.lastname: Bargatze
authors.forename: Zuoxiang
authors.initials: Z
authors.lastname: Xiao
authors.forename: Chunfa
authors.initials: C
authors.lastname: Jie
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Dawn
authors.initials: D
authors.lastname: Ruben
authors.forename: Julie
authors.initials: J
authors.lastname: Watson
authors.forename: Shukti
authors.initials: S
authors.lastname: Chakravarti
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Schneck
authors.forename: Abdel Rahim A
authors.initials: AR
authors.lastname: Hamad
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015704:CD4 Antigens; D016827:CD8 Antigens; D049109:Cell Proliferation; D053222:Fas Ligand Protein; D020869:Gene Expression Profiling; D017493:Leukocyte Common Antigens; D018655:Lymphocyte Count; D008232:Lymphoproliferative Disorders / Q000209:etiology; D051379:Mice; D016693:Receptors, Antigen, T-Cell, alpha-beta; D016176:T-Lymphocyte Subsets / Q000166:cytology*; D013601:T-Lymphocytes; D019014:fas Receptor
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D053222:Fas Ligand Protein; D016693:Receptors, Antigen, T-Cell, alpha-beta; D019014:fas Receptor; D017493:Leukocyte Common Antigens